The present invention relates to analysis for the presence of degenerative brain disease.
Increasing public and scientific concern has been expressed about the possibility of bovine spongiform encephalopathy (hereinafter BSE) being transmitted to the human population as a result of consumption of products derived from infected cattle. It has been postulated that British cattle have become infected with BSE as the result of eating feed including products derived from sheep that have been infected with scrapie. It has also been postulated that BSE has developed as the result of the nervous systems of cattle being damaged by pesticides. Regardless of the origins of the disease, it has been suggested that cattle suffering from BSE should be slaughtered and their carcasses should not be introduced into the human food chain.
Given that BSE takes typically five or more years to become manifest as the result of the behaviour of an infected animal, and that there has heretofore been no accepted method of assessing the probability of whether or not a particular cow is suffering from BSE other than examining the brain of the slaughtered animal, it has been suggested that the only safe approach to adopt which will in addition calm public fears about the safety of eating beef products is widespread slaughter. It is almost inevitable that such a policy will result in the slaughter of many thousands of cattle which are not infected with BSE.
It is known that information regarding the status of the central nervous system of mammals can be derived from the quantification of heart rate variability. For example, the paper "Respiratory sinus arrhythmia during recovery from isoflurane-nitrous oxide anaesthesia" by Donchin, Feld, and Porges, Anesth Analg 1985; 64:811-15 states that respiratory sinus arrhythmia (hereafter RSA) may provide a physiological index of the level of anaesthesia. That same paper refers to work dating back to as early as 1935 which indicated that RSA disappeared during the induction of ether anaesthesia.
It is also known that RSA is suppressed in diabetics. Details of a method for measuring RSA to enable the identification of diabetics which method relies upon the application of circular statistics to data derived from patients is given in the paper "RR-variation: the autonomic test of choice in diabetes", by Genovely and Pfeifer, Diabetes/Metabolism Reviews, volume 4, No. 3, 255-271(1988), John Wiley & Sons Inc.
Published International Patent Application No. WO92/06632 describes a method of monitoring the depth of anaesthesia by deriving a measurement of RSA from an analysis of the position of R-waves relative to the respiratory cycle and comparing the measured RSA with a reference value obtained from the analysed series of R-waves. This method provides a reliable indication of the depth of anaesthesia which is of use to an anaesthetist as the measure of the depth of anaesthesia can be obtained sufficiently quickly for that measurement to be used in the control of the administration of anaesthetics.
It is apparent from the above documents and references cited in those documents that RSA variation provides an indication of the state of the cardiovascular autonomic nervous system function and that the measurement of RSA may be of value in assessing depth of anaesthesia and in the identification of diabetics.
A review of recent publication has been conducted in an attempt to understand the structural changes which occur in the brains of mammals infected with BSE and similar spongiform degenerative brains diseases such as Creutzfeldt-Jakob disease (CJD). The results are summarised below.
A paper by M. Jeffery and W. G. Halliday entitled "Numbers of neurons in vacuolated and non-vacuolated neuroanatomical nuclei in bovine spongiform encephalopathy--affected brains", Journal of Comparative Pathology 110(3):287-293 reports studies of the brains of seven cows affected by BSE. These studies revealed that in infected animals there was an inconsistent degree of neuronal perikaryonal vacuolation in the dorsal vagal nucleus.
The abstract of a paper by A. Yagishita entitled "Computered tomography of Creutzfeldt-Jakob disease", in the Journal Rinsho Hoshasen, 34(11)P1317-25, 1989, noted marked atrophy of the cortex, brainstem and cerebellum.
A paper by G. A. H. Wells and J. W. Wilesmith entitled "The neuropathology and epidemiology of the bovine spongiform encephalopathy", Brain Pathology, 5(1):91-103, 1995 refers to the histopathological diagnosis of BSE, validated on a section of the medulla, and to neuronal loss in BSE which may make an important contribution to functional deficits.
RSA is a measure of the activity in the reflex loop defined between the lungs, brain and heart. The lungs feed data to the medulla of the brain stem which produces outputs transmitted via the vagal nerve to the heart to control heart rate. This reflex control loop is disrupted in diabetics as a result of damage to the vagal nerve and is disrupted by the administration of anaesthetic as a result of depression of brain stem activity. The present invention is based on a realisation that BSE and similar degenerative brain diseases are likely to disrupt the operation of the lungs/brain/heart reflex control loop and, given that RSA is an indicator of disruption to that control loop, it can also be used as an indicator of BSE.